Receptor tyrosine kinases (RTKs) are cell surface receptors of numerous important growth factors and hormones that involves in the intracellular signal transduction process. In addition to these intracellular regulatory roles, RTKs are also deeply involved in the onset and progression of many cancers. In such cancers, gene translocation occurs, resulting in a kinase fusion protein with non-specific activity.
Identification of translocation and mutation of cancers is crucial to the development of a selective new treatment method of fusion or mutant proteins and allows the development of anticancer drugs with low side effects and selective activity. For example, imatinib mesylate (Gleeve) is the first kinase inhibitor used as an anticancer agent and is effective in the treatment of CML (Chronic Myelogenous Leukemia) caused by the inhibition of BCR-ABL kinase.
As human RTKs, 58 types of RTKs belonging to 20 families have been identified (Blume-Jensen P, Hunter T. Oncogenic kinase signaling. Nature 2001; 411: 355-365). Among them, FMS kinase (c-fms; cellular Feline McDonough Sarcoma) is also called CSF-1R (colony-stimulating factor-1 receptor) and is a member of the gene group first isolated from the feline sarcoma virus Susan McDonough strains.
FMS kinase is a receptor for macrophage-colony-stimulating factor (M-CSF) and is classified as type III receptor tyrosine kinase (class III RTK) with Kit, Flt-3, and PDGFR. It is encoded by a primary oncogenic gene (c-fms proto-oncogene). M-CSF is also called CSF-1, and M-CSF is an important growth factor that involves in immune and inflammatory responses, bone metabolism and pregnancy. In addition, as FMS kinase participates in the process that monocytes activate into macrophages and differentiates into osteoclasts, it plays an important role in inflammation and bone erosion.
Therefore, overexpression of M-CSF or overexpression of its receptor, FMS, is closely associated with the growth and metastasis of cancer, and also is deeply associated with osteoporosis, rheumatoid arthritis, inflammatory diseases such as rheumatoid arthritis, Crohn's disease, etc. (El-Gamal M I et al., FMSKinase Inhibitors: Current Status and Future Prospects. Med Res Rev. 2013 May; 33 (3): 599-636).
Thus, there is a demand to develop a compound capable of inhibiting the activity of FMS kinase, and for example, such compound is disclosed in Korean Patent Publication No. 10-2014-0086002, Korean Patent Publication No. 10-2014-0002476, etc.
Therefore, the present inventors have studied the structure of a novel compound capable of inhibiting the activity of FMS kinase and found that N-(5-arylamido-2-methylphenyl)-5-methylisoquoxazole-4-carboxamide derivative has FMS kinase inhibitory activity, thereby completing the present invention.